Background: CHEDDA syndrome is a rare neurodevelopmental syndrome caused by heterozygous missense or indel variants in the HX repeat motif of ATN1 gene. To date, CHEDDA has been identified in a few ethnic groups, and only 17 patients have been reported in literature, and no case has been reported in any country or region in Asia. Methods: Trio-exome sequencing (Trio-ES) examination was conducted in aChinese girl with global developmental delay and in her parents. Sanger sequencing was performed to confirm the candidate variant.Results: This patient presented with mental and motor developmental delay, speech delay, and mild dysmorphic facial features, and had no epilepsy and visual impairment. Brain MRI did not show obvious structural abnormality.Through ES we identified a novel and de novo variant, c.3176_c.3177insGCACCT (p.Ser1059_His1060insHisLeu), within the HX motif of ATN1. No other pathogenic variant in another gene was found to support an alternative clinical and molecular diagnosis.Conclusions: This is the first described case of CHEDDA from China. Together with the available literature data, we found that either disruption of HX motif or alteration of the HX repeat number would lead to ATN1-associated CHEDDA.We also noted that CHEDDA is a clinical heterogenous syndrome, and patients carrying the same or similar variant might have different clinical manifestations and prognosis.

Background Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of metabolic disorders caused by abnormal protein or lpid glycoproteins. DPM2 is a subunit of a heterotrimeric complex (dolichol-phosphate-mannose synthase, DPMS), a key enzyme in glycosylation, and only four patients with DPM2-CDG have been reported. Methods Whole exome sequencing (WES) was applied to analyze a Chinese family with two daughters with developmental delay, milder intellectual disability, hypotonia and increased serum creatine kinase. In vitro functional study was performed to evaluate the impact of pathogenic genetic mutation . Results A homozygous mutation, c.197G > A (p.G66E) in exon 4 of DPM2 gene (NM_003863) was identified by whole exome sequencing. In vitro functional analysis demonstrated that this variant increased the expression level of DPM2 protein and western blot revealed a significant decrease in ICAM1, a universal biomarker for hypoglycosylation in patients with CDG, suggesting abnormal N-linked glycosylation. We also review the 4 previously reported patients carried homozygous or compound heterozygous mutations of DMP2 gene, and found that mutations within the region encoding the first domain is correlated with more severe clinical symptoms than ones within the second domain, establishing the possible correlation of genotypes and phenotype based on the localization of the variants. Conclusions our study broadens the mutation spectrum of DPM2 genes, expands the genetic and phenotypic relevance of DPM2 variants, and emphasizes the need of further functional studies to understand the underlying pathophysiology of the phenotype heterogeneity.